TSLP is an immune cytokine that induces dendritic cell-mediated CD4+ T cell responses with a proallogenic phenotype DC activated by TSLP play crucial role in the induction and maintenance of allergic inflammatory Th2 and mast cell responses by production of proallergenic cytokines, chemokines and costimulatory molecules that direct naïve T cells to become Th2 cells, producing 11-4, IL-5 and IL-13 critical mediators of allergic inflammation. Over-expression of TSLP in Atopic Dermatitis (AtD), Netherton Syndrome and Asthma indicates a crucial, role of this cytokine in the pathogenesis of these allergic inflammatory diseases. This is supported by animal models in which transgenic over-expression of TSLP in skin or lung as well as removal by gene targeting of negative regulators of TSLP results in allergic inflammatory diseases that closely resemble human atopic dermatitis or Asthma. The present invention provides engineered TSLP antibodies and uses thereof to treat inflammatory, and particularly allergic inflammatory disorders, including asthma and atopic dermatitis.
The present invention avoids potential deamidation problems of prior art antibodies. Deamidation of Asn (N) residues is a common degradation of proteins, and it can significantly impact protein structure and function. In antibodies, Asn (N) located in the CDRs can undergo deamidation rapidly and can result in changes in antibody-antigen interactions and therefore represents a serious concern during the development of antibody-based therapeutics. See, e.g., Vlaska et al., Analytical Biochemistry 392:145-154 (2009). Thus, it is important to avoid these potential deamidation problems in antibodies that are intended to be developed for human use. Further, it is important to avoid these problems without changing any of the important characteristics (such as binding affinity) of the antibody.